Abstract Out-of-hospital cardiac arrest (OHCA) is a common and debilitating public health problem. Neurologic injury is the major cause of morbidity and mortality in these patients with most resuscitated victims never regaining consciousness. Despite advances in resuscitation, over 70% of those who have circulation restored after OHCA die before hospital discharge. Therapies directed at heart and brain protection are needed to ameliorate many of the biochemical/cellular changes during the post resuscitation phase, which ultimately lead to cell death. The anion nitrite (NO2-) is converted to NO during hypoxia and during low pH, independent of NOS activity, making NO2- an ideal drug to increase NO bioavailability during ischemia and early in reperfusion when there is critical depletion. Therapeutic delivery of nitrite during ischemia or at time of reperfusion is cytoprotective in animal models of cardiac arrest. In an ongoing single-center pilot randomized trial of sodium nitrite (1-14 mg) IV vs. identically-appearing placebo in patients resuscitated from OHCA and transported to hospital, we found no significant deleterious effect of nitrite on hemodynamics. We believe that administration of sodium nitrite is feasible and not associated with serious adverse events in this population. These animal and human studies demonstrate the potential promise of nitrite as a therapy during resuscitation to reduce neurologic injury and improve survival. The overall goal of this study is to determine whether the administration of sodium nitrite is safe and efficacious during on going resuscitation for out-of-hospital cardiac arrest. We propose a two-stage clinical trial. The first phase will be an open-label dose finding trial to determine the optimal sodium nitrite dose to be administered at the time of resuscitation to achieve a plasma level of 10 ?M by hospital arrival. The second phase will be a placebo-control, randomized trial of the optimal single dose of sodium nitrite delivered during resuscitation to determine safety and efficacy. For both phases, all patients who have OHCA (both ventricular fibrillation (VF) and non-VF) in Seattle in which paramedics attempt cardiac resuscitation and have established IV access will be eligible. The primary safety outcome for the phase 2 trial will be survival to hospital admission and the secondary efficacy outcome will be survival to discharge.?